Modulation of vascular remodeling induced by a brief intraluminal exposure to the recombinant R7020 strain of Herpes simplex-1

OBJECTIVE: Vascular remodeling in response to injury or low shear stress (or both) is characterized by neointimal hyperplasia and luminal contraction. When profound, the response leads to restenosis after percutaneous endovascular intervention as well as to de novo stenosis in vein grafts. It has recently been reported that exposure of vein patches to neurovirulence-attenuated Herpes simplex virus-1 (HSV-1) decreases neointimal hyperplasia and increases luminal area. This experiment tested the hypothesis that R7020, a more highly attenuated mutant of HSV-1, would modulate the vascular remodeling response of experimental vein grafts chronically exposed to low shear stress. METHODS: The external jugular veins of 31 New Zealand white rabbits were clamped and intraluminally exposed to vehicle (phospate-buffered saline solution, n = 11), R7020 2.5 x 10(8) plaque forming units PFU]/mL (n = 8), or R7020 2.5 x 10(9) PFU/mL (n = 12) for 10 or 30 minutes at an average pressure of 80 mm Hg. After exposure, an end-to-side distal external jugular-to-common carotid artery anastomosis was created, resulting in a widely patent arteriovenous fistula. The external jugular was suture-ligated just proximal to the thoracic inlet, distal to a small 10- to 50-microm venous tributary, creating a reversed vein "graft" segment immediately and abruptly exposed to arterial pressure (48 +/- 3 mm Hg) and low shear stress (0.12 +/- .02 dyne/cm(2)). In the 29 animals (N = 31) that survived to harvest, 26 grafts were found to be patent and were analyzed further. Nine grafts were harvested within the first week after operation, snap frozen in liquid nitrogen, and assayed for the presence of the Herpes viral immediate-response protein ICP0 by Western blot analysis. The 17 remaining grafts were perfusion-fixed, excised, stained, and analyzed morphometrically by digital planimetry. RESULTS: In patent grafts, the hemodynamic environment of low shear stress was maintained (shear stress at harvest, 0.26 +/- .06 dyne/cm(2)). Western blot analysis revealed the presence of ICP0 in R7020-exposed vein grafts after 2, 3, 7, and 14 days; ICP0 was not detected in unexposed vein grafts or adjacent carotid arteries. After 4 weeks, vein grafts exposed to R7020 exhibited a statistically significantly increased ratio of luminal radius to wall thickness, indicating altered remodeling (vehicle, 6.7 +/- 1.3; R7020 2.5 x 10(8), 9.1 +/- 1.3; R7020 2.5 x 10(9) ratio, 11.3 +/- 1.4; P < .05 for high dose compared with vehicle). CONCLUSION: A brief exposure of the neurovirulence-attenuated HSV-1 strain R7020 results in an increased ratio of luminal radius to wall thickness in experimental vein grafts chronically exposed to low shear stress.